Project Summary/Abstract: Effector T cells mediate protective tumor immunity. The goal of tumor immune therapy including check-point blockade and immune vaccination and adoptive effector T cell is to engender long-term protective effector T cell immunity, and cause tumor eradiation in patients with cancer. To this end, effector T cells must traffic into and retain within the tumor microenvironment with potent effector function. Interestingly, the central scientific efforts in the field of tumor immunology are focused on designing different combinatorial therapeutic regimens with PD-L1/PD-1 blockade, exploring new types of CAR-T cells, and evaluating a variety of potential neoantigen cancer vaccination. However, T cells are highly dysfunctional and susceptible to apoptosis in the tumor microenvironment. Our current knowledge of tumor associated effector T cell survival and functionality, and its underlying molecular mechanisms remain poorly understood in patients with cancer. This inadvertent deficiency significantly tempers our efforts toward understanding basic human effector T cell biology, establishing and evaluating immune therapeutic regimens and tumor vaccines in treating patients with cancer. It is essential to conduct comprehensive molecular and functional research on the nature of effector T cell survival and function in the human tumor microenvironment. Abnormal epigenetic pattern correlates to effector T cell malfunction in tumor. However, their potential causal and mechanistic connection is poorly defined. S-adenosylmethionine (SAM) links one-carbon metabolism to methylation status. Using patients with colon cancer and mice bearing different types of cancer, our preliminary studies demonstrated that tumor cells altered methionine metabolism in CD8+ T cells, resulting in insufficient intracellular methionine, low methyl donor SAM, and diminished H3K79me2. Loss of H3K79me2 led to reduced STAT5 expression and activation, resulting in impaired T cell-mediated tumor immunity. Mechanistically, tumor cells were addicted to methionine and outcompeted T cells for methionine via high expression of SLC43A2, a methionine transporter. These data revealed previously unknown mechanisms of association between specific amino acid metabolism, epigenetic alteration and T cell immunity in the tumor microenvironment and identified cancer methionine transporter(s) as a potential novel immunotherapeutic target. Based on this surprising and novel finding, we hypothesize that dysfunctional methionine metabolism is not only a novel immune evasion mechanism, but also a key link between specific histone pattern alteration and survival/functional gene circuits in effector T cells in the tumor microenvironment. We propose two specific aims to mechanistically, functionally, and clinically test our central hypothesis that (1) methionine metabolic circuit controls effector T cell survival and functional potency in the tumor microenvironment, and (2) particular tumor solute carrier family (SLC) member(s) affects T cell methionine metabolism, function and protective immunity.